Active implantable medical device for atrial stimulation for the treatment of heart failure with preserved ejection fraction

ABSTRACT

An active implantable medical device includes digital processor circuits configured to sense right and left atrial depolarizations and deliver left atrial stimulation pulses according to a stimulation protocol. The stimulation protocol includes delivering a left atrial stimulation pulse at an inter-atrial coupling interval. The inter-atrial coupling interval is a coupling interval shorter than the sinus rhythm coupling interval, so as to deliver a premature pulse. The protocol further includes delivering a not premature left-atrial stimulation pulse during an immediately subsequent cardiac cycle, at an inter-atrial coupling interval corresponding to the sinus rhythm coupling interval. The protocol also includes assessing the right atrial coupling interval between the right atrial depolarizations and comparing the right atrial coupling interval to the sinus rhythm coupling interval. And finally, modifying an adjustable controlling parameters if necessary according to the result of the comparison. The device has no means for collecting and analyzing the endocardial acceleration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to French PatentApplication No. 13/61199, filed Nov. 15, 2013, which is herebyincorporated by reference herein in its entirety.

BACKGROUND

The invention relates to “active implantable medical devices” as definedby Directive 90/385/EEC of 20 Jun. 1990 of the Council of the EuropeanCommunities, specifically implants to continuously monitor heart rhythmand deliver if necessary electrical pulses to the heart for stimulation,resynchronization and/or defibrillation in case of rhythm disorderdetected by the device. It more particularly relates to devices fortreating heart failure (HF), as an alternative or in addition to thetreatment of cardiac rhythm disorders.

This therapy is designed to resynchronize the contraction of the heartchambers (atrium and ventricle) so as to improve the patient's conditionby optimizing the phases of the hemodynamic cycle. The cycle includespre-ejection, isovolumetric contraction, systolic ejection,isovolumetric relaxation and finally filling of the cavity.

Most of these devices implement a technique called “CRT” (CardiacResynchronization Therapy) or “BVP” (Bi-Ventricular Pacing) fordelivering, as necessary, electrical pulses needed to ensure joint andcontinuous stimulation of the two (left and right) ventricles toresynchronize them. This biventricular resynchronization techniquehowever addresses only one of the forms of heart failure, known as“systolic failure”. In this form of the disease, the heart muscle isunable to provide the force necessary to ensure adequate cardiac output,and the patient shows signs of expansion resulting in a delay of leftventricular depolarization. CRT biventricular pacing is then used toresynchronize the ventricles and make more uniform cardiac contraction.

In the other form of heart failure called “diastolic failure” or“preserved ejection fraction heart failure” (HFpEF, Heart Failure withpreserved Ejection Fraction), there is no desynchronization of theventricles; it comes from a failure in the left ventricular filling.Biventricular CRT stimulation will be ineffective in this case. Thiscondition affects about 40% of heart failure patients, and there is noknown effective treatment to remedy to it.

This form of disease in some patients may be the result of a disorder ofconduction in the atria (inter-atrial block), which delays thedepolarization, and therefore the contraction of the left atrium (OG)with respect to the right atrium (OD). However, as atrioventricularconduction pathways are not altered, depolarization and contraction ofthe right (VD) and left (VG) ventricles occur within a reasonable time,without synchronization VD-VG. It is between the contraction of the leftatrium and that of the left ventricle that the inter-atrial block OD-OGgenerates a poor sequencing OG-VG. The delay of the contraction of theleft atrium has for consequence that it contracts substantially at thesame moment as the left ventricle, and therefore cannot properly fulfillits function and contribute to the left ventricular active filling.

To treat this heart failure with preserved ejection fraction, atechnique of atrial overdriving, pathology, has been proposed. This isdescribed for example in the US7494921B1, which describes permanentlystimulating the left atrium to a frequency slightly above thespontaneous sinus rhythm frequency (i.e. the rate of the right atrium),thereby systematically causing premature depolarization of the leftatrium and restoring an almost normal OG-VG sequence.

Specifically, in this technique, the device regularly measures thespontaneous rhythm of the patient and applies a sequence of pacingpulses at a slightly faster rate, arbitrarily programmed to cause aprematurity in the order of 50 to 100 ms compared to an atrial couplinginterval corresponding to the spontaneous sinus rhythm. After severalcycles at this accelerated pace, the frequency gradually slows untilreappearance of spontaneous activity, then the overdriving method isrepeated in the same way.

In the description of this technique, the “atrial coupling interval” or“atrial coupling” is defined as the time interval separating twospontaneous (in sinus rhythm, also designated as “PP interval”) orstimulated consecutive atrial events. The applied stimulation frequencythus varies continuously between values wherein it is too fast(overdriving period) or too slow (period of reappearance of spontaneousrhythm, with OD-VD synchronization), without real monitoring of theeffectiveness of a possible return to a proper synchronization of theleft cavities.

It should also be noted that this pacing mode may interfere with thefilling of the right cavities. In fact, due to premature stimulation ofthe left atrium, the OD-VD synchronization is significantly altered in amanner which may be incompatible with satisfactory filling of the rightventricle (we will clarify these aspects in the detailed description).Improvement therapy in left ventricular filling is thus likely to induceadverse effects on the filling of the right ventricle, so in the cavitythat was not affected by the pathology to be treated.

Moreover, this technique requires the presence of a right ventricularsensing lead, so as to ensure that overdriving is controlled on thebasis of the actual atrial activity, and not on signals detected at theatrium but actually due to the depolarization of the ventricles(far-field signals).

Another technique is described in EP 2471575 A1 (Sorin CRM SAS) whichimplements a sensor for collecting an endocardial acceleration signal(EA). The EA signal is analyzed to detect the presence of a specificcomponent reflecting atrial contraction (EA4 component) and to identifythe instant of occurrence of this component. If the EA4 component ispresent, this means that the sequencing of atrial contractions iscorrect because otherwise (i.e., left atrial contractions too late), theEA4 component would be mixed in the component of the EA signalcorresponding to the immediately following ventricular contraction (EA1component). The atrial stimulation interval (AA interval) is thendynamically adjusted depending on the result of this analysis.

However, this technique requires an implantable lead provided with anendocardial acceleration sensor, and a generator capable of processingthe EA signals delivered by such a sensor.

SUMMARY

One object of the invention is to propose a new technique for treatmentof heart failure with preserved ejection fraction in patients withmechanical inter-atrial delay, which overcomes the drawbacks of themethods proposed so far and which does not require the use of methodsfor collecting and analyzing an EA signal.

Another object of the invention is to propose a technique that ensuresrecovery of diastolic function in a method that is relatively simple (interms of resources used) and reactive (high efficiency obtained cycle tocycle).

The invention operates by a unique atrial pacing to restore asatisfactory OG-VG sequencing (sequencing the contraction of the leftatrium compared to that of the left ventricle), so that the atrium canproperly fulfill its function of completion of the filling of the leftventricle.

To implement the disclosed embodiments, there is no need for ventricularpacing and/or ventricular depolarization detection methods. The lattercan of course exist, for example in the case of a multi-site pacemakerproviding stimulation of the right ventricle or of the two ventricles inaddition to the stimulation of the atria (triple or quadruple chamberpacemakers). But these ventricular methods are not involved in thetreatment of heart failure with preserved ejection fraction, which aimsto overcome pre-existing conduction condition between the atria, namelyan inter-atrial block resulting in an excessive delay in conductionbetween the right atrium and the left atrium.

Specifically, the invention provides a device including digitalprocessor circuits configured for: sensing of right atrialdepolarizations; sensing of left atrial depolarizations; delivering leftatrial stimulation pulses; and delivering, selectively on the basis ofadjustable controlling parameters, of premature the left atrialstimulation pulses, by applying a short inter-atrial coupling, shorterthan the sinus rhythm coupling interval

A feature of the invention is that the device has no means forcollecting and analyzing the endocardial acceleration, and the digitalprocessor is configured so as to:

-   -   after a first cardiac cycle without left atrial stimulation,        deliver a left atrial stimulation pulse during an immediately        consecutive second cardiac cycle, with application of an        inter-atrial coupling,    -   the inter-atrial coupling applied during the second immediately        consecutive cardiac cycle being a short coupling shorter than        the sinus rhythm coupling interval, so that the left atrial        stimulation pulse delivered during the second cardiac cycle is a        premature pulse;    -   deliver a not premature left-atrial stimulation pulse during a        third cardiac cycle immediately subsequent to the second cardiac        cycle, with application of an inter-atrial coupling        corresponding to the sinus rhythm coupling interval (D1), so as        to:        -   assess the right atrial coupling interval between the right            atrial depolarizations during the second and third cardiac            cycles;        -   compare the right atrial coupling interval thus assessed to            the sinus rhythm coupling interval; and    -   modify or not, at least one of the adjustable controlling        parameters according to the result of the comparison.

According to various advantageous subsidiary characteristics:

-   -   the modified or not controlling parameter depending on the        result of the comparison is the short inter-atrial coupling;    -   in that case, if the right atrial coupling interval is less than        the sinus rhythm coupling interval (D1), the digital processor        is further configured so as to change by one step the short        inter-atrial coupling, then deliver a premature left atrial        stimulation pulse during a subsequent cardiac cycle, with        application of the short inter-atrial coupling changed by one        step;    -   on detection of a predetermined event, the digital processor is        further configured so as to        -   inhibit any delivery of left atrial stimulation pulse during            at least one cardiac cycle;        -   measure on at least one cardiac cycle the atrial escape            interval and the inter-atrial delay;        -   and store this escape interval as a coupling interval of the            sinus rhythm for the determination of the short inter-atrial            coupling and inter-atrial delay corresponding to the sinus            rhythm coupling interval in the subsequent cycles;    -   the predetermined event is the expiry of a predetermined fixed        timing interval; and    -   the predetermined event is the detection of the crossing of a        predetermined threshold by the variation in the atrial coupling        interval.

According to one embodiment, there is an active implantable medicaldevice, the device comprising digital processor circuits configured tosense right and left atrial depolarizations and deliver, selectively onthe basis of adjustable controlling parameters, left atrial stimulationpulses according to a stimulation protocol. The stimulation protocolincludes, after a first cardiac cycle without left atrial stimulation,delivering a left atrial stimulation pulse during an immediatelyconsecutive second cardiac cycle at an inter-atrial coupling interval.The inter-atrial coupling interval applied during the second immediatelyconsecutive cardiac cycle is a short coupling interval shorter than thesinus rhythm coupling interval, so that the left atrial stimulationpulse delivered during the second cardiac cycle is a premature pulse.The protocol further includes delivering a not premature left-atrialstimulation pulse during a third cardiac cycle immediately subsequent tothe second cardiac cycle, at an inter-atrial coupling intervalcorresponding to the sinus rhythm coupling interval. The protocol alsoincludes assessing the right atrial coupling interval between the rightatrial depolarizations during the second and third cardiac cycles andcomparing the right atrial coupling interval to the sinus rhythmcoupling interval. And finally, modifying at least one of the adjustablecontrolling parameters if necessary according to the result of thecomparison. The device has no means for collecting and analyzing theendocardial acceleration.

According to another embodiment, there is a method for resynchronizationof the contraction of the heart chambers. The method includes sensingright atrial depolarizations and sensing left atrial depolarizations.The method also includes delivering, selectively on the basis ofadjustable controlling parameters, left atrial stimulation pulsesaccording to a stimulation protocol. The stimulation protocol includes,after a first cardiac cycle without left atrial stimulation, deliveringa left atrial stimulation pulse during an immediately consecutive secondcardiac cycle at an inter-atrial coupling interval. The inter-atrialcoupling interval applied during the second immediately consecutivecardiac cycle is a short coupling interval shorter than the sinus rhythmcoupling interval, so that the left atrial stimulation pulse deliveredduring the second cardiac cycle is a premature pulse. The protocolfurther includes delivering a not premature left-atrial stimulationpulse during a third cardiac cycle immediately subsequent to the secondcardiac cycle, at an inter-atrial coupling interval corresponding to thesinus rhythm coupling interval; and assessing the right atrial couplinginterval between the right atrial depolarizations during the second andthird cardiac cycles. The protocol also includes comparing the rightatrial coupling interval to the sinus rhythm coupling interval andmodifying at least one of the adjustable controlling parameters ifnecessary according to the result of the comparison.

According to yet another embodiment, there is a cardiacresynchronization system including a stimulation/detection electrode forpositioning in the right atrium of a heart and a stimulation/detectionelectrode for positioning in the left atrium of the heart, wherein theelectrodes are configured to be coupled to an implantable medicaldevice. The implantable medical device includes a generator and digitalprocessor circuits. The digital processor circuits are configured tosense right atrial depolarizations from the stimulation/detectionelectrode and sense left atrial depolarizations from thestimulation/detection electrode. The digital processor circuits arefurther configured to deliver a left atrial stimulation pulse during acardiac cycle immediately following a preceding cardiac cycle with noleft atrial stimulation, the left atrial stimulation pulse delivered atan inter-atrial coupling interval. The inter-atrial coupling interval isa short coupling interval shorter than the sinus rhythm couplinginterval. The digital processor circuits are further configured todeliver a second left-atrial stimulation pulse during an immediatelysubsequent cardiac cycle at an inter-atrial coupling intervalcorresponding to the sinus rhythm coupling interval. The digitalprocessor circuits are further configured to assess the right atrialcoupling interval between the right atrial depolarizations during theconsecutive cardiac cycles and compare. the right atrial couplinginterval to the sinus rhythm coupling interval. After comparing, thedigital processor circuits are configured to determine whether to modifythe inter-atrial coupling interval based on the result of thecomparison.

DRAWINGS

Further features, characteristics and advantages of the presentinvention will become apparent to a person of ordinary skill in the artfrom the following detailed description of preferred embodiments of thepresent invention, made with reference to the drawings annexed, in whichlike reference characters refer to like elements and in which:

FIG. 1 schematically illustrates the position of the different sitesinvolved in the cyclic, spontaneous or stimulated, electrical activityof the heart.

FIG. 2 is a series of timing diagrams illustrating various signalscharacterizing cardiac activity during two successive cycles, in thecase of a known overdriving technique.

FIG. 3 is a diagram illustrating, in one exemplary embodiment, thesequencing of atrial and ventricular detections and stimulations in foursuccessive cardiac cycles, in the case of a device operating accordingto the teachings of the invention.

FIG. 4 is a flowchart describing the method to deliver cardiac pacingaccording to an embodiment of the invention.

FIG. 5 is a block diagram illustrating an embodiment of an implantablemedical device that can be used to implement various features presentedherein.

DETAILED DESCRIPTION

Regarding its software aspects, the invention may be implemented byappropriate programming of the controlling software of a knownstimulator, for example a cardiac pacemaker, resynchronizer ordefibrillator, including methods of acquisition of a signal provided byendocardial leads. The invention may notably be applied to implantabledevices, such as that of the Reply, Ovatio and Paradym families,manufactured and commercialized by Sorin CRM, Clamart, France.

These devices include programmable microprocessor circuitry to receive,format and process electrical signals collected by implantableelectrodes, and deliver stimulation pulses to these electrodes. It ispossible to download in it by telemetry software that is stored inmemory and executed to implement the functions of the invention that aredescribed below. The adaptation of these devices to the implementationof the functions of the invention is within the skill in the art andwill not be described in detail.

FIG. 1 shows a diagram of the heart with its four chambers: right atriumOD, right ventricle VD, left atrium OG and left ventricle VG. Thecoordinated contraction of the different cavities is originated in thesinus node NS, then the depolarization wave is conducted to theatrioventricular node NAV (conduction represented by arrow 10), thenfrom this node to the His bundle FH, and finally to tissues of right andleft ventricles VD and VG, causing contraction thereof. Moreover, thedepolarization wave originated from the sinus node NS causes contractionof the right atrium OD and, after inter-atrial conduction (conductionrepresented by arrow 12) to the left atrium, causes contraction of thelatter.

In the case of a patient suffering from heart failure with preservedejection fraction, the atrioventricular conduction (arrow 10, from thesinus node NS to the atrioventricular node NAV) is usually preserved, aswell as the conducting paths to ensure synchronous contraction of boththe left (VG) and right (VD) ventricles. However, when atrial conduction(arrow 12) is altered, it causes a delay in the depolarization andtherefore in the contraction of the left atrium OG compared to theventricles. This induces a poor timing of the contraction of the leftatrium OG relative to the left ventricle VG, with a substantiallyconcomitant contraction of the two cavities. Therefore, the left atriumOG cannot properly fulfil its function, which is to complete the fillingof the left ventricle VG.

The implantable device 14 includes a generator connected to astimulation/detection electrode 16 at the right atrium OD, and astimulation/detection electrode 18 at the left atrium OG. The electrode18 may be positioned in particular in the coronary sinus or in a veinbelonging to the coronary network such as the Marshall vein, or on theinter-atrial septum, or directly into the left atrium after puncture ofthe inter-atrial septum. In a particular implementation described at theend of the present description, or for purposes other thanimplementation of the invention, the device may also include aventricular lead 20 such as an endocardial lead implanted in the rightventricle VD.

The overdriving conventional technique usually implemented with thistype of device to remedy a heart failure with preserved ejectionfraction is illustrated in FIG. 2. Plots of various records collectedduring two successive cardiac cycles are shown in this figure: the firstin spontaneous rhythm, the second with overdriving. These recordscorrespond to the following branches: distal and proximal electrodes onthe right atrium (RAd and RAp), right ventricle (RV), distal andproximal electrodes on the left atrium (LAd and LAp), and distal andproximal electrodes on the His bundle (HISd and HISp), roughlycorresponding to the depolarization of the left ventricle (including theHISd branch).

At the first cardiac cycle there is a delay, compliant, of 256 msbetween the spontaneous depolarization of the right ventricle (VD) andthe depolarization of the right atrium (OD). By contrast, the OD-OGdelay between the respective depolarization of both atria has anexcessive and pathological value of 194 ms, which has the effect ofleaving a gap of 78 ms between the depolarization of the left atrium(OG) and the contraction of the left ventricle (VG), an interval tooshort to provide adequate filling of the left ventricle. In extremecases, the contraction of the left atrium and of the left ventricle caneven be almost concurrent, negating the role of the atrium in thefilling of the ventricle.

In the second cardiac cycle, which is a cycle with overdriving, thedevice paces the left atrium at a given time (T) having a deliberateprematurity ΔT from the normal sinus rhythm interval corresponding tothe cycle to cycle coupling interval OD-OD. This premature stimulationof the left atrium will restore an almost physiological sequencing OG-VG(174 ms). However, the OD-VD sequencing is significantly changed, sincethis delay is now 154 ms instead of 256 ms, which may result indeleterious effects regarding the right cavity hemodynamic.

FIG. 3 is a diagram illustrating the sequencing of atrial andventricular detections and stimulations during four successive cardiaccycles, in the case of a device operating according to the teachings ofthe invention. On this diagram are represented various markerscorresponding to the sinus rhythm NS, to the right atrial rhythm OD, tothe left atrial rhythm OG, and to the ventricular rhythm VD/VG (it isassumed that there is no delay between the depolarization of the rightventricle and that of the left ventricle).

The basic principle of the invention is to control the device withstimulation of the left atrium, controlled to avoid any overdrivingeffect and thus not to change the right atrioventricular sequence.Initially (Cycle 1), the initial influx originated from the sinus nodespreads through the right atrium. The OD1 marker corresponds to thedetection by the right atrial lead with a delay Δ from the beginning ofthe cycle, a delay corresponding to the propagation delay to the rightatrium from the sinus node.

This influx then depolarizes the atrioventricular node and reaches theventricles (VDG1 marker). It also spreads to the left atrium (OG1marker), with a significant delay in the pathology of heart failure withpreserved ejection fraction, so that in the shown example,depolarization of the left atrium (OG1 marker) and of the ventricles(VDG1 marker) are substantially concurrent.

The cycle is repeated (Cycle 2), with an interval of atrial coupling D1corresponding to sinus rhythm. The sequencing default of the left atriumoccurs, with a too long interval D2 between the depolarizations of theright (marker OD2) and left (marker OG2) atria.

At the next cycle (cycle 3), in accordance with the invention, astimulation is delivered to the left atrium (StimOG3 marker) after aperiod A from the previous depolarization of the left atrium (OG2Marker). This duration is chosen to generate a predetermined prematurityPM (relative to the marker OG3′ of the depolarization that would haveoccurred with the normal atrial coupling interval), calculated to (1)ensure that the OG3-VDG3 interval is long enough to establish a normalsequencing of the left cavities, and (2) not to change the sequencingOD3-VDG3 of the right cavities.

To do this, the device determines the durations D1 (OD1-OD2) and D2(OD2-OG2) during cycles 1 and 2, and calculates prematurity:

PM=D2−a

a being a time interval chosen to correspond, e.g., to the propagationdelay between the sinus node and the right atrium (delay indicated bythe arrow 10 in FIG. 1) so that the depolarization of the left atrium isnot synchronous with that of the right atrium, but slightly delayedcompared to the latter. That delay can be fixed, for example, 50 ms, orprogrammable. Alternatively, a may be zero if it is desirable that bothatria are synchronous, or even be negative if one wants the contractionof the left atrium occurs above that of the right atrium.

This prematurity PM corresponds, as explained above, to a durationA=D1−PM counted from the previous depolarization of the left atrium (OG2marker) before delivering of a stimulation to the left atrium (StimOG3marker).

If a left atrial post-stimulation blanking period is applied, thepreferred is a positive a interval which positions the left atrialstimulation just after the right atrial detection, thereby preventingthe application of a post-stimulation blanking that would jeopardizethis detection.

During the next cycle (Cycle 4) the device delivers stimulation to theleft atrium (StimOG4 marker), but with an inter-atrial interval D1corresponding to the interval OD1-OD2 that was measured in previouscycles before the left atrium is stimulated. The device then measuresthe interval OD3-OD4 (interval D3) and compares this interval to theinterval OD1-OD2 (interval D1):

-   -   if D1=D3, this means that the atrial coupling is maintained, and        that the (premature) stimulation of the left atrium in the        previous cycle did not cause indirect depolarization of the        right atrium;    -   if D3<D1, this means that prematurity is too large, and changed        the depolarization of the right atrium; which is sought to be        avoided.

The stimulation of the left atrium will then be suspended for one (ormore) cycle(s), and the stimulation sequence will then be restarted, butwith a reducing of the prematurity of a variation step (that is to sayextending the duration A). This may be repeated as necessary until thereis a sequence n such that the interval ODn−ODn+1=OD1−OD2.

On a regular basis, e.g. every minute, or in case of significant changein the right atrial coupling interval (interval D1 change above athreshold), the above method is repeated in order to dispose of a cyclewithout stimulation of the left atrium, which will serve as a reference.

A block diagram of a flowchart 400 of delivery of cardiac pacingaccording to an exemplary embodiment of the invention is shown in FIG.4. After a first cardiac cycle in which no left atrial pacing OG isdelivered, the device (e.g., an implantable medical device) delivers apremature stimulation pulse OG during the second cardiac cycle (step405), immediately following the first cardiac cycle. The prematurestimulation OG is adjusted to cause the application of a shortinter-atrial coupling shorter than the sinus rhythm coupling interval.

The device then applies a not premature pacing pulse OG during a thirdcardiac cycle (step 410), which immediately follows the second cardiaccycle. The not premature stimulation pulse OG is adjusted so as to causethe application of an inter-atrial coupling which corresponds to thecoupling interval of the sinus period.

The device then determines a right atrial coupling interval OD betweenthe depolarizations of the right atrium in the second and third cycles(step 415). The device compares the coupling interval OD to the sinusrhythm coupling interval (step 420). Depending on the result of thecomparison, the device determines if it is necessary and/or how tomodify one or more parameters of the stimulation applied to the leftatrium during subsequent cardiac cycles (step 425). One or more steps ofthe flowchart 400 may be repeated after changing of the settings, tofurther modify the parameters and/or to optimize the stimulation of theleft atrium.

A block diagram of an exemplary embodiment of a device 500 that can beused to implement various features described above is shown in FIG. 5.The device 500 may be an implantable medical device adapted to beimplanted in a subject, e.g. a patient. The device 500 includes agenerator 505 configured to generate stimulation signals to tissue, forexample a cardiac tissue, nerve tissue, etc.). Detection signals can bereceived from one or more electrodes 540 coupled to generator 505 viawire 535 or a wireless interface. In some embodiments, the generator 505can be connected to the electrodes 540 by cables. Also, in someembodiments the generator 505 may be connected to electrodes and includea power source such as a battery 530. In some embodiments, the generator505 may include one or more wireless transceivers configured to allowthe generator 505 to communicate wirelessly with one or more otherdevices (e.g., devices external to the patient). For example, a wirelesstransceiver may communicate with a computing device for general purposeor special purpose (e.g., a desktop computer, a tablet, etc.),particularly in a hospital or in a clinical environment for transmittingsignals to and from the external computer device, for example to receivecontrol signals configured for controlling the detection/stimulationsettings for the generator 505 and/or provide data relating to thedetection/stimulation to the external computing device.

The generator 505 includes a processor 510 and a memory 515. Theprocessor 510 can be of any standard type or a processor for specialpurposes that may be integrated into the housing of the generator 505.The memory 515 can include any appropriate type of storage mediumreadable by a machine for storing machine-executable instructions 520machine and/or other data 525. The instructions 520 can be executed bythe processor 510 to implement various operations described in thispaper. For example, such storage media readable by a machine may includeRAM, ROM, EPROM, EEPROM, flash memory or any other means which can beused to transfer or store program code in the form of machine executableinstructions or of data structures that can be read by a machine with aprocessor. Any combination of the above is also included in the scope ofwhat is referred to as a storage medium readable by machine. Themachines or computer-readable storage supports mentioned here do notinclude the temporary supports, such as signals in free field.

In some embodiments, the memory 515 may include one or more modules withinstructions configured to cause the processor 510 to perform variousfunctions such as those described above. For example, the memory 515 mayinclude a stimulation module configured to control the generation and/ortransmission of stimulation pulses (e.g. the atrial pacing pulses) toelectrodes 540. The memory 515 may include a module configured to detectthe information collected by the electrodes 540 and assess the responseto be provided (for example, assessing the atrial coupling intervaland/or comparing the right atrial coupling interval and the sinus rhythminterval). The detection unit may be configured to modify one or moreparameters of the stimulation depending on this evaluation. Theparameters can also be stored in the memory 515.

1. An active implantable medical device, the device comprising digitalprocessor circuits configured to: sense right atrial depolarizations;sense left atrial depolarizations; and deliver, selectively on the basisof adjustable controlling parameters, left atrial stimulation pulsesaccording to a stimulation protocol, the stimulation protocolcomprising: after a first cardiac cycle without left atrial stimulation,delivering a left atrial stimulation pulse during an immediatelyconsecutive second cardiac cycle at an inter-atrial coupling interval,wherein the inter-atrial coupling interval applied during the secondimmediately consecutive cardiac cycle is a short coupling intervalshorter than the sinus rhythm coupling interval, so that the left atrialstimulation pulse delivered during the second cardiac cycle is apremature pulse; delivering a not premature left-atrial stimulationpulse during a third cardiac cycle immediately subsequent to the secondcardiac cycle, at an inter-atrial coupling interval corresponding to thesinus rhythm coupling interval; assessing the right atrial couplinginterval between the right atrial depolarizations during the second andthird cardiac cycles; comparing the right atrial coupling interval tothe sinus rhythm coupling interval; and modifying at least one of theadjustable controlling parameters if necessary according to the resultof the comparison; wherein the device has no means for collecting andanalyzing the endocardial acceleration.
 2. The device of claim 1,wherein the adjustable controlling parameter is the short inter-atrialcoupling interval.
 3. The device of claim 2, wherein, if the result ofthe comparison indicates the right atrial coupling interval is less thanthe sinus rhythm coupling interval, the digital processor is furtherconfigured to modify the adjustable controlling parameter to: change byone step the short inter-atrial coupling interval; and deliver apremature left atrial stimulation pulse during a subsequent cardiaccycle at the short inter-atrial coupling interval changed by one step.4. The device of claim 1 wherein, on detection of a predetermined event,the digital processor is further configured to: inhibit any delivery ofleft atrial stimulation pulse during at least one cardiac cycle; measureon at least one cardiac cycle the atrial escape interval and theinter-atrial delay; and store this escape interval as a couplinginterval of the sinus rhythm for the determination of the shortinter-atrial coupling interval and the inter-atrial delay correspondingto the coupling interval of the sinus rhythm in the subsequent cycles.5. The device of claim 4, wherein the predetermined event is the expiryof a predetermined fixed timing interval.
 6. The device of claim 4,wherein the predetermined event is the detection of the crossing of apredetermined threshold by the variation in the atrial couplinginterval.
 7. A method for resynchronization of the contraction of theheart chambers, the method comprising: sensing right atrialdepolarizations; sensing left atrial depolarizations; and delivering,selectively on the basis of adjustable controlling parameters, leftatrial stimulation pulses according to a stimulation protocol, thestimulation protocol comprising: after a first cardiac cycle withoutleft atrial stimulation, delivering a left atrial stimulation pulseduring an immediately consecutive second cardiac cycle at aninter-atrial coupling interval, wherein the inter-atrial couplinginterval applied during the second immediately consecutive cardiac cycleis a short coupling interval shorter than the sinus rhythm couplinginterval, so that the left atrial stimulation pulse delivered during thesecond cardiac cycle is a premature pulse; delivering a not prematureleft-atrial stimulation pulse during a third cardiac cycle immediatelysubsequent to the second cardiac cycle, at an inter-atrial couplinginterval corresponding to the sinus rhythm coupling interval; assessingthe right atrial coupling interval between the right atrialdepolarizations during the second and third cardiac cycles; comparingthe right atrial coupling interval to the sinus rhythm couplinginterval; and modifying at least one of the adjustable controllingparameters if necessary according to the result of the comparison. 8.The method of claim 7, wherein the stimulation protocol is executed tocause an interval between left atrial contraction and ventricularcontraction long enough to establish a normal sequencing of the leftcavities while causing no change the sequencing of the right atrialcontraction and ventricular contraction.
 9. The method of claim 7,wherein the adjustable controlling parameter is the short inter-atrialcoupling interval.
 10. The method of claim 9, further comprisingmodifying the short inter-atrial coupling interval if the right atrialcoupling interval is less than the sinus rhythm coupling interval. 11.The method of claim 10, wherein the modifying step comprises: changingby one step the short inter-atrial coupling interval; and delivering apremature left atrial stimulation pulse during a subsequent cardiaccycle at the short inter-atrial coupling interval changed by one step.12. The method of claim 7, further comprising: detecting a predeterminedevent; inhibiting any delivery of left atrial stimulation pulse duringat least one cardiac cycle; measuring on at least one cardiac cycle theatrial escape interval and the inter-atrial delay; and storing thisescape interval as a coupling interval of the sinus rhythm for thedetermination of the short inter-atrial coupling interval and theinter-atrial delay corresponding to the coupling interval of the sinusrhythm in the subsequent cycles.
 13. The method of claim 12, wherein thepredetermined event is the expiry of a predetermined fixed timinginterval.
 14. The method of claim 12, wherein the predetermined event isthe detection of the crossing of a predetermined threshold by thevariation in the atrial coupling interval.
 15. The method of claim 7,wherein the premature pulse is premature to a naturally occurringdepolarization at the sinus rhythm by a prematurity value (PM=D1−a),wherein the prematurity value is less than the interval between the leftatrial depolarization and the right atrial polarization during the firstcardiac cycle at an interval a so that the depolarization of the leftatrium is not synchronous with that of the right atrium, but slightlydelayed.
 16. A cardiac resynchronization system, comprising: astimulation/detection electrode for positioning in the right atrium of aheart; a stimulation/detection electrode for positioning in the leftatrium of the heart; wherein the electrodes are configured to be coupledto an implantable medical device, the implantable medical devicecomprising a generator and digital processor circuits configured to:sense right atrial depolarizations from the stimulation/detectionelectrode; sense left atrial depolarizations from thestimulation/detection electrode; and deliver a left atrial stimulationpulse during a cardiac cycle immediately following a preceding cardiaccycle with no left atrial stimulation, the left atrial stimulation pulsedelivered at an inter-atrial coupling interval, wherein the inter-atrialcoupling interval is a short coupling interval shorter than the sinusrhythm coupling interval; deliver a second left-atrial stimulation pulseduring an immediately subsequent cardiac cycle at an inter-atrialcoupling interval corresponding to the sinus rhythm coupling interval;assess the right atrial coupling interval between the right atrialdepolarizations during the consecutive cardiac cycles; compare the rightatrial coupling interval to the sinus rhythm coupling interval; anddetermine whether to modify the inter-atrial coupling interval based onthe result of the comparison.
 17. The system of claim 16, wherein thedigital processor circuits are further configured to modify theinter-atrial coupling interval if the right atrial coupling interval isless than the sinus rhythm coupling interval.
 18. The system of claim17, wherein the digital processor circuits are further configured tomodify the inter-atrial coupling interval by: changing by one step theshort inter-atrial coupling interval; and delivering a premature leftatrial stimulation pulse during a subsequent cardiac cycle at the shortinter-atrial coupling interval changed by one step.
 19. The system ofclaim 16, wherein the digital processor circuits are further configuredto: detect a predetermined event; inhibit delivery of left atrialstimulation pulse during at least one cardiac cycle; measure on at leastone cardiac cycle the atrial escape interval and the inter-atrial delay;and store the escape interval as a coupling interval of the sinus rhythmfor the determination of the short inter-atrial coupling interval andthe inter-atrial delay corresponding to the coupling interval of thesinus rhythm in the subsequent cycles.
 20. The system of claim 16,further comprising a ventricular lead for implantation in the right orleft ventricle.